Human papilloma virus (HPV) is a small, non-enveloped virus that infects human epidermis and mucosal cells. At present, more than 100 kinds of HPV subtypes have been found. According to the pathogenicity, HPV is divided into low-risk type and high-risk type. The continuous infection of high-risk HPVs is closely related to the pathogenesis of some malignancies. Clinical trials, molecular biology studies and etiology studies have been shown that HPV infection is a major factor in the pathogenesis of cervical cancer (zur Hausen H. Papillomaviruses and cancer: from basic studies to Clinical application. Nat Rev Cancer 2002; 2: 342-50). A large number of epidemiological studies have been shown that HPV can be detected in 97% of cervical cancer, and HPV16 and HPV18 subtypes are highly correlated with the occurrence of cervical cancer. In addition to cervical cancer, HPV is also highly related to the occurrence of other cancers, such as oral cancer, esophageal cancer, head and neck cancer, rectum, anal cancer, lung cancer, and breast cancer. Therefore, the development of HPV genetic engineering vaccine is one of the important means for the prevention and treatment of cervical cancer and some other malignant tumors associated with HPV infection.
HPV vaccine can be divided into two categories of preventive vaccines and therapeutic vaccines. After the HPV infection, the body will produce neutralizing antibodies for HPV capsid protein L1 and L2 which can effectively protect the host from infection. Thus, preventive HPV vaccines are generally composed of viral capsid protein L1 or L1-L2 and can be self-assembled into hollow virus-like particles (VLPs) free of viral DNA in cells (Kirnbauer R, Taub J, Greenstone H, et al. Efficient self-assembly of human papillomavirus type 16 L1 and L1-L2 into virus like particles. J Virol [J]. 1993,67: 6929-36.). VLPs have the same antigenic epitope as the intact virus, and in a way, which can replace the natural virus to stimulate the body's CD4+ lymphocyte-mediated humoral immune response and induce the production of a protective antibody against natural viruses, and can effectively protect the host from virus infection (Schiller J, Lowy D. Papillomavirus-like particle vaccines . JNatl Cancer Inst Monogr 2001; (28): 50-4).
The two existing preventive vaccines which are Merck's tetravalent vaccine of Gardasil and GlaxoSmithKline's bivalent vaccine of Cervarix, can effectively prevent the occurrence of cervical cancer by reducing the HPV infection ratio, but these vaccines can not treat HPV infection, nor can they treat HPV-associated malignant diseases (Trimble CL, Frazer IH. Development of therapeutic HPV vaccines. Lancet Oncol 2009; 10: 975-80). After HPV infection, viral DNA can be integrated into the human genome, and expressoncogenic proteins in the host cell. E6 and E7 proteins are generally overexpressed in cervical epithelial cells of the patients with high-grade cervical lesions and the cancer, leading to over-proliferation and malignant transformation of infected cells. As the virus oncogenic proteins E6 and E7 can be continuously expressed in the host tumor cells, and therefore the antigen target of immunotherapy for the HPV infection-related diseases can be provided. Thus, the therapeutic vaccine mainly uses HPV early proteins E6 and E7 as the target protein. For the treatment after HPV infection, the tumor residual lesions, cervical atypical hyperplasia (CIN) caused by HPV infection can be removed, the transition of low-risk lesions to high-risk type and cancer can be blocked (Nonn M, Schinz M, Zumbach K , Pawlita M, Schneider A, Dürst M, Kaufmann AM. Dendritic cell-based tumor vaccine for cervical cancer I: in vitro stimulation with recombinant protein-pulsed dendritic cells induces specific T cells to HPV16 E7 or HPV18 E7. J Cancer Res Clin Oncol. 2003; 129 (9): 511-20.).
HPV therapeutic vaccines can be divided into five categories: vector vaccines, peptide vaccines, protein vaccines, gene vaccines and cell vaccines. Protein vaccines can be divided into fusion protein vaccines and chimeric vaccines. Because a lesion may be caused by multiple types of HPV infection, the development of the preventive and/or therapeutic vaccines for variety types of HPV virus is a major challenge in HPV vaccine research, and possessing an important application value and future.